: Cannabis is the most widely-used illicit drug in the U.S., and over 1 million people are treated for cannabis dependence annually. Given the potential for dependence as well as deleterious effects of chronic use, there is an urgent need to better understand the mechanisms supporting cannabis use, in order to develop therapies to reduce such use. There are several animal models in which reliable intravenous self-administration of cannabinoids such as ?9THC (THC) has been demonstrated. Most human use, however, occurs through inhalation of cannabis smoke, which contains numerous cannabinoids aside from THC, some of which is psychoactive and may interact with THC to alter its reinforcing effects. Hence, an animal model that employs cannabis smoke self-administration would more closely mimic the conditions of actual human use, and would open new directions of research on cannabis use and abuse. The long-term goal of this research program is to use rodent models to investigate the reinforcing effects of smoked cannabis, with the ultimate goal of developing therapies for reducing cannabis use/abuse. As the first step toward this goal, the objective of this CEBRA R21 project is to develop and validate a system by which rats can self-administer cannabis smoke. To our knowledge, there are no reports of self-administration of smoked drugs of abuse in rodents; however, there have been several demonstrations in primates of reliable self-administration of smoked drugs of abuse, including cocaine and heroin. In addition, we have preliminary data showing development of dependence following passive cannabis smoke administration in rats, demonstrating the efficacy of cannabis smoke as a drug delivery vehicle in this species. On the basis of these published and preliminary data, our central hypothesis is that rats will self-administer cannabis smoke, and that smoke self-administration behavior will be similar to that reported for intravenous cannabinoids and other drugs of abuse. We have designed an apparatus that will allow precisely-calibrated, response-contingent delivery of cannabis smoke using experimental designs similar to those employed with other drugs of abuse. We will use this apparatus to determine whether rats will reliably show operant responding for cannabis smoke delivery, and whether this responding is sensitive to smoke THC content and CB1 receptor activation, as well as to cues predictive of smoke delivery. We have also developed multiple strategies to increase the likelihood of obtaining self-administration behavior. Successful development of a rodent cannabis smoke self-administration model will lay the groundwork for a larger research program on neurobehavioral mechanisms of cannabis smoking. In addition, this model could be adapted for use with other smoked drugs of abuse (e.g., tobacco).